3-Aryl 2-oxazolidinones, their process of preparation and their therapeutical application

ABSTRACT

Compounds having the formula ##STR1## wherein R 1  is hydrogen or CONHR 7  and R 7  is methyl or isopropyl, 
     And wherein 
     When R 1  is hydrogen: R is p-nitro, p-cyano; p-aldehydo; p-acetyl; m-ethyl; m-nitro; m-bromo; 3,4-dimethyl; m-NH 2  ; p-methylamino; p-dimethylamino; p-diethylamino; p-methylbenzylamino; p-pyrrolidino; p-piperidino; SR 4  in para position in which R 4  is alkyl having 1 to 4 carbon atoms or cyclohexyl; OR 5  is para position in which R 5  is alkyl having 2 to 7 carbon atoms, cyclohexyl, cyclohexylmethyl, acetylmethyl; cyanomethyl, alkene-2 yl having 3 to 5 carbon atoms, butene-3 yl, cyclohexene-1 methyl, propargyl, butyne-2 yl, ##STR2## in which n is one or 2 and when n is one, R 6  is hydrogen, o-fluoro, o-methyl, m-chloro, m-fluoro, m-methyl, m-trifluoromethyl, p-chloro, p-bromo-, p-fluoro, p-cyano, p-nitro or p-dimethylamino and when n is 2, R 6  is hydrogen; and 3-methyl-4-benzyloxy: 
     When R 1  is CONHR 7  and R 7  is methyl: R is m-trifluoromethyl; m-bromo; p-chloro; p-fluoro; 3,4-dichloro; p-thiomethyl; p-acetyl; OR 8  in para position wherein R 8  is alkyl having 2 to 5 carbon atoms, cyanomethyl, acetylmethyl, propargyl or ##STR3## in which R 9  is hydrogen, m-chloro, m-bromo, m-fluoro, p-fluoro, p-chloro or p-nitro; 
     And when R 1  is CONHR 7  and R 7  is isopropyl; R is m-trifluoromethyl or p-benzyloxy. 
     The compounds are prepared by cyclizing 1-phenylamino-2,3-propandiol derivatives to form 5-hydroxymethyl-3 phenyl-2-oxozolidinone derivatives. The 5-hydroxymethyl group can be transformed to --CH 2  OCONHR 7  by reaction with methyl isocyanate or isopropyl isocyanate. The compounds possess psychotropic, particularly antidepressant, activity.

The present invention relates to aryl-3-oxazolidinones-2, a process for preparing them and their application in therapeutics, particularly in the psychotopic field.

The compounds of the invention correspond more exactly to the following formula (I): ##STR4## in which R₁ represents: EITHER A HYDROGEN ATOM, IN WHICH CASE R may be:

A p-nitro, p-cyano, p-aldehydo or p-acetyl radical; an m-ethyl, m-nitro, or m-bromo group; or two methyl groups in meta and para positions;

An m-NH₂ group or ##STR5## IN THE PARA POSITION AND IN WHICH THE COUPLE (R₂, R₃) can have the following meanings: (H, CH₃), (CH₃, CH₃), (C₂ H₅, C₂ H₅), ##STR6## or form with the nitrogen atom to which they are bonded a pyrrolidino or piperidino radical;

a --SR₄ group in the para position and in which R₄ represents an alkyl radical having 1 to 4 carbon atoms or a cyclohexyl radical;

a --OR₅ group in the para position and in which R₅ represents:

an alkyl radical having 2 to 7 carbon atoms,

a cyclohexyl, cyclohexylmethyl, acetylmethyl, or cyanomethyl radical,

an alkene-2 yle radical having 3 to 5 carbon atoms, butene-3 yle or cyclohexene-1 methyl,

a propargyl or butyne-2 yle radical,

a radical of ##STR7## in which n is equal to 1 and R₆ represents a hydrogen atom, a fluorine atom or a methyl group when it is in the ortho position; a chlorine atom, a fluorine atom, a methyl or trifluoromethyl group when it is in the meta position; and a chlorine, bromine or fluorine atom, a cyano, nitro or dimethyl-amino group when it is in the para position; or n is equal to 2 and R₆ designates a hydrogen atom; or

two groups, one methyl in the meta position, the other benzyloxy in the para position;

or a CO NH R₇ group where R₇ designates a methyl group in which case R may be:

an m-trifluoromethyl or m-bromo group; a p-chloro or p-fluoro radical; two atoms of chlorine in meta and para positions; a p-thiomethyl or p-acetyl radical;

a --O R₈ group in the para position and in which R₈ designates:

an alkyl radical having from 2 to 5 carbon atoms, a cyanomethyl or acetylmethyl radical, a propargyl radical, or

a radical of ##STR8## in which R₉ represents a hydrogen atom, a chlorine, bromine or fluorine atom when it is in the meta position, and a fluorine atom, a chlorine atom or a nitro group when it is in the para position;

or where R₇ designates an isopropyl group in which case R designates an m-trifluoromethyl or p-benzyloxy radical.

The process for preparing compounds of the invention of formula (I) in which R₁ is a hydrogen atom, consists in cyclizing, by ethyl carbonate action, a 1-phenylamino-2,3-propanediol of formula: ##STR9## in which R' represents: a p-nitro, p-cyano, p-aldehydo- p-acetyl, m-methyl, m-nitro or m-bromo radical; or two methyl groups in meta and para positions; ##STR10## in para position and where the couple (R'₂, R'₃) can have the following meanings: (CH₃, CH₃), (C₂ H₅, C₂ H₅), ##STR11## or form with the nitrogen atom to which they are bonded a pyrrolidino or piperidino radical;

an S--R₄ group in the para position and where R₄ has the same meaning as in formula (I);

a p-ethoxy or p-benzyloxy group; or

two groups, one methyl in the meta position, the other benxyloxy in the para position,

which leads to compounds of formula: ##STR12## then possibly to subject the compound of formula (Ia): in which R' represents an m-nitro radical, to a catalytic reduction in an autoclave and in the presence of palladium on charcoal, which leads to the compound of formula: ##STR13## in which R' represents a p-N-methyl N-benzylamino group, to a hydrogenolysis action in alcohol in the presence of palladium on charcoal, which leads to the compound of formula: ##STR14## and in which R' represents a p-benzyloxy group, to a hydrogenolysis action in alcohol in the presence of palladium on charcoal, which leads to the compound of formula: ##STR15## which is condensed with a product corresponding to one of the following formulas: ##STR16## in which R'₅ has the same meaning as R₅ in formula I except for the ethyl and benzyl values, which leads to the compounds of formula: ##STR17##

The compounds of formula II, in part novel, are, as to them, obtained by condensation, in methanol or ethanol, of anilines of formula: ##STR18## in which R' has the same meaning as in formula II, with glycidol of formula: ##STR19##

The compounds of formula (I) in which R₁ represents a CONHR₇ group where R₇ is a methyl or isopropyl group are, for their part, obtained by the action of an alkyl isocyanate of formula:

    R'.sub.1 --N CO                                            (VI)

in which R'₁ designates a methyl or isopropyl group on an oxazolidinone of formula (I) in which R₁ represents a hydrogen atom and R can be:

an m-trifluoromethyl or m-bromo radical; a p-chloro or p-fluoro radical; two chlorine atoms in meta and para positions; a p-thiomethyl or p-acetyl radical;

a --OR₈ group in the para position and in which R₈ designates:

an alkyl radical having 2 to 5 atoms of carbone, a cyanomethyl or acetylmethyl radical, a propargyl radical or a radical of ##STR20## in which R₉ represents a hydrogen atom or a chlorine, bromine or fluorine atom when it is in the meta position, and a fluorine atom, a chlorine atom or a nitro group when it is in the para position.

The examples below are given solely as an illustration of the invention.

EXAMPLE 1: 3-ethylthiophenylamino 1,2-propanediol Code No. 760465

A solution of 12.6 g (0.082 mole) of p-ethylthioaniline and 6.1 g (0.082 mole) of glycidol in 80 ml of ethanol is heated under reflux for 7 hours. Then, it is evaporated and the residue is chromatographed on silica (elution with a mixture of chloroform (80)-acetone(20)).

Yield: 43%

Melting point: <50° C.

Empirical formula: C₁₁ H₁₇ NO₂ S

Elementary analysis:

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 58.12     7.54      6.16                                        Obtained (%)   57.96     7.45      6.30                                        ______________________________________                                    

EXAMPLE 2: 5-hydroxymethyl-3-metanitrophenyl-2 oxazolidinone Code No. 740511

A mixture of 48 g (0.2 mole) of 3-metanitrophenylamino-1,2-propanediol (prepared according to a mode of operation similar to that of example 1), 200 ml of ethyl carbonate and 8 ml of triethylamine is heated at 100°-110° C. for 5 hours. The product obtained is filtered and recrystallised in absolute alcohol.

Melting point: 140° C.

Yield: 73%

Empirical formula: C₁₀ H₁₀ N₂ O₅

Molecular weight: 238.20

Elementary analysis:

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 50.42     4.23      11.76                                       Obtained (%)   50.54     4.39      11.81                                       ______________________________________                                    

In the same way we can obtain compounds corresponding to the following code numbers and shown in table 1 below: 750341 - 750710 - 740564 - 740512 - 760271 - 760133 - 760311 - 760375 - 760474 - 760349 - 760082 - 760466 - 760483 - 760473 - 760600 - 760621 - 760037 - 770017 - 770054 - 760670 - 760167.

EXAMPLE 3: 5-hydroxymethyl 3-metaaminophenyl 2-oxazolidinone Code No. 750079

A solution of 28 g (0.08 mole) of 5-hydroxymethyl 3-metanitrophenyl 2-oxazolidinone prepared in the previous example is hydrogenated, in an autoclave, under a pressure of 2 to 3 kg, at room temperature and in the presence of palladium on charcoal at 10%, in 400 ml of dioxane. The reaction is finished in 5 hours. Then it is filtered, the filtrate evaporated and the residue crystallised in alcohol.

Melting point: 118° C.

Yield: 10%

Empirical formula: C₁₀ H₁₂ N₂ O₃

Molecular weight: 208.21

Elementary analysis:

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 57.68     5.81      13.46                                       Obtained (%)   57.39     5.77      13.22                                       ______________________________________                                    

EXAMPLE 4: 5-hydroxymethyl 3-p-N-methylaminophenyl 2-oxazolidinone Code No. 760395

A solution of 19 g (0.061 mole) of 5-hydroxymethyl 3-p-N-benzyl N-methylaminophenyl 2-oxazolidinone, prepared according to a mode of operation similar to that of example 2, is hydrogenolysed in an autoclave at 50° C., under a pressure of 4 kg for 5 hours, in 400 ml of alcohol, in the presence of 0.6 ml of hydrochloric acid 6.4 N and 3 g of palladium on charcoal at 10%. It is filtered, the filtrate is evaporated, and the residue is taken up with an aqueous solution of bicarbonate of soda, then it is filtered and recrystallised in methanol.

Melting point: 174° C.

Yield: 6%

Empirical formula: C₁₁ H₁₄ N₂ O₃

Elementary analysis:

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 59.45     6.35      12.61                                       Obtained (%)   59.29     6.39      12.61                                       ______________________________________                                    

EXAMPLE 5: 5-hydroxymethyl 3-p-cyanomethyloxyphenyl 2-oxazolidinone Code No. 760651 1st step: 5-hydroxymethyl 3-p-hydroxyphenyl 2-oxazolidinone Code No. 760172

A solution of 132.5 g (0.44 mole) of 5-hydroxymethyl 3-p-benzyloxyphenyl 2-oxazolidinone, prepared according to a mode of operation similar to that of example 2, is hydrogenolysed in an autoclave, between 45° and 50° C., under a pressure of 2 kg for 6 hours, in 1.5 litre of alcohol, in the presence of 13 g of palladium on charcoal at 10%. It is filtered, the filtrate is evaporated and recrystallised in isopropyl alcohol.

Melting point: 183° C.

Yield: 82%

Empirical formula: C₁₀ H₁₁ NO₄

Elementary analysis:

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 57.41     5.30      6.70                                        Obtained (%)   57.62     5.62      6.69                                        ______________________________________                                    

2nd step: 5-hydroxymethyl 3-p-cyanomethyloxyphenyl 2-oxazolidinone Code No. 760651

A mixture of 15 g (0.07 mole) of 5-hydroxymethyl 3-p-hydroxyphenyl 2-oxazolidinone prepared in the previous step, 7.6 g (0.1 mole) of chloracetonitrile, 38 g (0.28 mole) of potassium carbonate and 1 g of potassium iodide is brought to reflux for 8 hours in 450 ml of acetone. It is filtered, the filtrate is evaporated and the residue crystallised in absolute alcohol.

Melting point: 98° C.

Yield: 67%

Empirical formula: C₁₂ H₁₂ N₂ O₄

Molecular weight: 248.23

Elementary analysis:

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 58.06     4.87      11.29                                       Obtained (%)   57.91     4.92      11.21                                       ______________________________________                                    

In the same way, we can obtain the compounds corresponding to the following code numbers and listed in table I below: 760116 - 760303 - 760304 - 760414 - 760396 - 760549 - 760534 - 760314 - 770018 - 760306 - 760827 - 760650 - 760535 - 760536 - 760307 - 760877 - 770063 - 770104 - 760337 - 760317 - 760547 - 760556 - 760574 - 760548 - 760537 - 760533 - 760881 - 760622 - 760937 - 760432 - 760453 - 760652.

EXAMPLE 6: 5-N-methylcarbamoyloxymethyl 3-p-cyanomethyloxyphenyl 2-oxazolidinone Code No. 760660

A solution of 7 g (0.028 mole) of 5-hydroxymethyl 3-p-cyanomethyloxyphenyl 2-oxazolidinone prepared in the 2nd step of example 5, and 4.8 g (0.084 mole) of methyl isocyanate in 30 ml of 1,2-dichlorethane is heated at 110° C. in a sealed tube for 3 hours. Then the solvent is evaporated, the residue crystallised in ether and recrystallised in methanol.

Melting point: 90° C.

Yield: 70%

Empirical formula: C₁₄ H₁₅ N₃ O₅

Molecular weight: 305.28

Elementary analysis:

    ______________________________________                                                      C       H         N                                               ______________________________________                                         Calculated (%) 55.08     4.95      13.77                                       Obtained (%)   54.91     4.84      13.68                                       ______________________________________                                    

In the same way we can obtain the compounds corresponding to the following code numbers and listed in table I below: 740704 - 750479 - 750726 - 750685 - 750820 - 740711 - 760786 - 760104 - 760663 - 760662 - 760712 - 760819 - 760658 - 760729 - 760676 - 760717 - 760730 - 760409 - 760723 - 760728 - 760809 - 760733 - 760731.

Tables I and II below give respectively the compounds of formula (I) of the invention and new intermediate compounds (II), these later being prepared according to a mode of operation similar to that of example 1.

                                      TABLE I                                      __________________________________________________________________________      ##STR21##                                                                                                           Mel-                                     Code                              Mole-                                                                              ting   Elementary analysis               Num-                      Empirical                                                                              cular                                                                              point                                                                             Yield                                                                              Calculated                                                                              Obtained (%)             ber  R          R.sub.1   formula weight                                                                             (° C.)                                                                     (%) C  H  N  C  H  N                  __________________________________________________________________________     740704                                                                             3CF.sub.3   CONHCH.sub.3                                                                             C.sub.13 H.sub.13 F.sub.3 N.sub.2 O.sub.4                                              318.25                                                                             115                                                                               75  49.06                                                                             4.12                                                                               8.80                                                                             48.79                                                                             3.95                                                                               8.61              750479                                                                             4Cl         "         C.sub.12 H.sub.13 ClN.sub.2 O.sub.4                                                    284.70                                                                             110                                                                               52  50.62                                                                             4.60                                                                               9.84                                                                             50.84                                                                             4.62                                                                               9.68              750726                                                                             3Br         "         C.sub.12 H.sub.13 BrN.sub.2 O.sub.4                                                    329.15                                                                              90                                                                               75  43.79                                                                             3.98                                                                               8.51                                                                             43.89                                                                             4.08                                                                               8.36              750685                                                                             4F          "         C.sub.12 H.sub.13 FN.sub.2 O.sub.4                                                     268.24                                                                             100                                                                               70  53.73                                                                             4.89                                                                              10.44                                                                             53.76                                                                             5.00                                                                              10.25              750820                                                                             3,4diCl     "         C.sub.12 H.sub.12 Cl.sub.2 N.sub.2 O.sub.4                                             319.15                                                                             123                                                                               66  45.16                                                                             3.79                                                                               8.78                                                                             45.04                                                                             3.63                                                                               8.49              740711                                                                             3CF.sub.3                                                                                   ##STR22##                                                                               C.sub.15 H.sub.17 F.sub.3 N.sub.2 O.sub.4                                              346.30                                                                             121                                                                               61  52.02                                                                             4.95                                                                               8.09                                                                             52.26                                                                             5.06                                                                               8.03              750341                                                                             3,4diCH.sub.3                                                                              H         C.sub.12 H.sub.15 NO.sub.3                                                             221.25                                                                             129                                                                               73  65.14                                                                             6.83                                                                               6.33                                                                             65.15                                                                             6.80                                                                               6.32              750710                                                                             3Br         H         C.sub.10 H.sub.10 BrNO.sub.3                                                           272.90                                                                             100                                                                               64  44.14                                                                             3.70                                                                               5.14                                                                             44.21                                                                             3.94                                                                               5.20              740564                                                                             4NO.sub.2   H         C.sub.10 H.sub.10 N.sub.2 O.sub.5                                                      238.20                                                                             154                                                                               68  50.42                                                                             4.23                                                                              11.76                                                                             50.42                                                                             4.26                                                                              11.59              740512                                                                             3C.sub.2 H.sub.5                                                                           H         C.sub.12 H.sub.15 NO.sub.3                                                             221.25                                                                              97                                                                               70  65.14                                                                             6.83                                                                               6.33                                                                             64.88                                                                             6.78                                                                               6.22              760271                                                                             4CN         "         C.sub.11 H.sub.10 N.sub.2 O.sub.3                                                      218.21                                                                             130                                                                               20  60.54                                                                             4.62                                                                              12.84                                                                             60.49                                                                             4.42                                                                              12.86              760133                                                                              ##STR23##  "         C.sub.12 H.sub.16 N.sub.2 O.sub.3                                                      236.26                                                                             150                                                                               25  61.00                                                                             6.83                                                                              11.86                                                                             60.72                                                                             7.07                                                                              11.77              760311                                                                              ##STR24##  "         C.sub.14 H.sub.20 N.sub.2 O.sub.3                                                      264.32                                                                              95                                                                               13  63.61                                                                             7.63                                                                              10.60                                                                             63.76                                                                             7.85                                                                              10.85              760375                                                                              ##STR25##  "         C.sub.18 H.sub.20 N.sub.2 O.sub.3                                                      312 142                                                                               79  69.21                                                                             6.45                                                                               8.97                                                                             69.47                                                                             6.66                                                                               9.16              760474                                                                              ##STR26##  H         C.sub.14 H.sub.18 N.sub.2 O.sub.3                                                      262.30                                                                             168                                                                               42  64.10                                                                             6.92                                                                              10.68                                                                             63.92                                                                             6.59                                                                              10.91              760349                                                                              ##STR27##  H         C.sub.15 H.sub.20 N.sub.2 O.sub.3                                                      276.33                                                                             170                                                                               39  65.19                                                                             7.30                                                                              10.14                                                                             64.89                                                                             7.27                                                                              10.44              760082                                                                             4 SCH.sub.3 H         C.sub.11 H.sub.13 NO.sub.3 S                                                           239.29                                                                             133                                                                               62  55.21                                                                             5.48                                                                               5.85                                                                             54.95                                                                             5.38                                                                               5.92              760786                                                                             4 SCH.sub.3 CONHCH.sub.3                                                                             C.sub.13 H.sub.16 N.sub.2 O.sub.4 S                                                    296.34                                                                             120                                                                               78  52.69                                                                             5.44                                                                               9.45                                                                             52.59                                                                             5.23                                                                               9.60              760466                                                                             4 SC.sub.2 H.sub.5                                                                         H         C.sub.12 H.sub.15 NO.sub.3 S                                                           253.31                                                                             110                                                                               66  56.89                                                                             5.97                                                                               5.53                                                                             56.82                                                                             5.85                                                                               5.48              760473                                                                             4 SC.sub.4 H.sub.9 (n)                                                                     H         C.sub.14 H.sub.19 NO.sub.3 S                                                           281.37                                                                             106                                                                               52  59.76                                                                             6.81                                                                               4.98                                                                             59.76                                                                             6.59                                                                               4.81              760483                                                                              ##STR28##  "         C.sub.13 H.sub.17 NO.sub.3 S                                                           267.34                                                                              85                                                                               45  58.40                                                                             6.41                                                                               5.24                                                                             58.50                                                                             6.13                                                                               4.96              760600                                                                             4 SC.sub.3 H.sub.7 (n)                                                                     "         "       "   102                                                                               "   "  "  "  58.68                                                                             6.58                                                                               5.20              760621                                                                              ##STR29##  "         C.sub.16 H.sub.21 NO.sub.3 S                                                           307.40                                                                              82                                                                               57  62.51                                                                             6.89                                                                               4.56                                                                             62.73                                                                             7.00                                                                               4.55              760037                                                                             4 OC.sub.2 H.sub.5                                                                         "         C.sub.12 H.sub.15 NO.sub.4                                                             237.25                                                                             133                                                                               91  60.75                                                                             6.37                                                                               5.90                                                                             60.81                                                                             6.54                                                                               5.89              760116                                                                              ##STR30##  "         C.sub.13 H.sub.17 NO.sub.4                                                             251.27                                                                              74                                                                               56  62.14                                                                             6.82                                                                               5.57                                                                             62.29                                                                             6.77                                                                               5.48              760303                                                                             4 OC.sub.3 H.sub.7 (n)                                                                     "         "       "   139                                                                               72  "  "  "  61.88                                                                             7.16                                                                               5.62              760304                                                                             4 OC.sub.4 H.sub.9 (n)                                                                     "         C.sub.14 H.sub.19 NO.sub.4                                                             265.30                                                                             122                                                                               68  63.38                                                                             7.22                                                                               5.28                                                                             63.53                                                                             7.21                                                                               5.37              760414                                                                              ##STR31##  "         "       "   110                                                                               30  "  "  "  63.41                                                                             7.25                                                                               5.19              760396                                                                             4 OC.sub.5 H.sub.11 (n)                                                                    "         C.sub.15 H.sub.21 NO.sub.4                                                             279.33                                                                             124                                                                               48  64.49                                                                             7.58                                                                               5.01                                                                             64.43                                                                             7.75                                                                               4.86              760549                                                                             4 OC.sub.6 H.sub.13 (n)                                                                    H         C.sub.16 H.sub.23 NO.sub.4                                                             293.35                                                                             115                                                                               76  65.50                                                                             7.90                                                                               4.78                                                                             65.55                                                                             8.00                                                                               4.50              760534                                                                             4 OC.sub.7 H.sub.15 (n)                                                                    "         C.sub.17 H.sub.25 NO.sub.4                                                             307.38                                                                             110                                                                               65  66.42                                                                             8.20                                                                               4.56                                                                             66.44                                                                             7.91                                                                               4.54              760314                                                                              ##STR32##  "         C.sub.16 H.sub.21 NO.sub.4                                                             291.37                                                                             124                                                                               15  65.96                                                                             7.27                                                                               4.81                                                                             65.73                                                                             7.29                                                                               4.91              770018                                                                             4 OC.sub.4 H.sub.9 (t)                                                                     "         C.sub.14 H.sub.19 NO.sub.4                                                             265.30                                                                              93                                                                               52  63.38                                                                             7.22                                                                               5.28                                                                             63.41                                                                             7.25                                                                               5.19              760104                                                                             4 OC.sub.2 H.sub.5                                                                         CONHCH.sub.3                                                                             C.sub.14 H.sub. 18 N.sub.2 O.sub.5                                                     294.30                                                                             110                                                                               52  57.13                                                                             6.16                                                                               9.52                                                                             57.02                                                                             6.22                                                                               9.51              760663                                                                             4 OC.sub.3 H.sub.7 (n)                                                                     "         C.sub.15 H.sub.20 N.sub.2 O.sub.5                                                      308.33                                                                              96                                                                               72  58.43                                                                             6.54                                                                               9.09                                                                             58.53                                                                             6.48                                                                               9.04              760662                                                                             4 OC.sub.4 H.sub.9 (n)                                                                     "         C.sub.16 H.sub.22 N.sub.2 O.sub.5                                                      322.35                                                                              84                                                                               80  59.61                                                                             6.88                                                                               8.69                                                                             59.60                                                                             6.91                                                                               8.66              760712                                                                             4 OC.sub.4 H.sub.9 (iso)                                                                   "         "       "    89                                                                               88  "  "  "  59.33                                                                             6.87                                                                               8.61              760819                                                                             4 OC.sub.5 H.sub.11 (n)                                                                    CONHCH.sub.3                                                                             C.sub.17 H.sub.24 N.sub.2 O.sub.5                                                      336.38                                                                              90                                                                               56  60.70                                                                             7.19                                                                               8.33                                                                             60.45                                                                             7.22                                                                               8.44              760306                                                                             4OCH.sub.2CHCH.sub.2                                                                       H         C.sub.13 H.sub.15 NO.sub.4                                                             249.26                                                                             109                                                                               76  62.64                                                                             6.07                                                                               5.62                                                                             62.69                                                                             6.14                                                                               5.68              760827                                                                             4OCH.sub.2CHCH                                                                             H         C.sub.14 H.sub.17 NO.sub.4                                                             263.28                                                                             150                                                                               62  63.86                                                                             6.51                                                                               5.32                                                                             63.74                                                                             6.52                                                                               5.31                   CH.sub.3 (trans)                                                          760650                                                                              ##STR33##  "         C.sub.15 H.sub.19 NO.sub.4                                                             277.31                                                                             100                                                                               34  64.96                                                                             6.91                                                                               5.05                                                                             64.77                                                                             6.97                                                                               4.87              760535                                                                              ##STR34##  "         C.sub.14 H.sub.17 NO.sub.4                                                             263.28                                                                              82                                                                               74  63.86                                                                             6.51                                                                               5.32                                                                             64.09                                                                             6.57                                                                               5.22              760536                                                                             4 O(CH.sub.2).sub.2                                                                        H         C.sub.14 H.sub.17 NO.sub.4                                                             263.28                                                                             116                                                                               18  63.86                                                                             6.51                                                                               5.32                                                                             63.97                                                                             6.81                                                                               5.55                   CHCH.sub.2                                                                760307                                                                             4 OCH.sub.2C CH                                                                            "         C.sub.13 H.sub.13 NO.sub.4                                                             247.24                                                                             130                                                                               79  63.15                                                                             5.30                                                                               5.67                                                                             63.08                                                                             5.53                                                                               5.78              760658                                                                             "           CONHCH.sub.3                                                                             C.sub.15 H.sub.16 N.sub.2 O.sub.5                                                      304.29                                                                             122                                                                               71  59.20                                                                             5.30                                                                               9.21                                                                             58.95                                                                             5.43                                                                               9.31              760877                                                                             4 OCH.sub.2C C                                                                             H         C.sub.14 H.sub.15 NO.sub.4                                                             261.27                                                                             140                                                                               58  64.36                                                                             5.79                                                                               5.36                                                                             63.98                                                                             5.80                                                                               5.18                   CH.sub.3                                                                  770063                                                                              ##STR35##  "         C.sub.17 H.sub.21 NO.sub.4                                                             303.35                                                                              99                                                                               45  67.31                                                                             6.98                                                                               4.62                                                                             67.41                                                                             6.97                                                                               4.78              770104                                                                              ##STR36##  "         C.sub.17 H.sub.23 NO.sub.4                                                             305.36                                                                             130                                                                               80  66.86                                                                             7.59                                                                               4.59                                                                             66.74                                                                             7.50                                                                               4.70              760167                                                                              ##STR37##  "         C.sub.17 H.sub.17 NO.sub.4                                                             299.31                                                                             150                                                                               94  68.21                                                                             5.73                                                                               4.68                                                                             68.03                                                                             5.75                                                                               4.41              760337                                                                              ##STR38##  "         C.sub.17 H.sub.16 ClNO.sub.4                                                           333.76                                                                             152                                                                               66  61.17                                                                             4.83                                                                               4.20                                                                             60.98                                                                             4.70                                                                               4.44              760317                                                                              ##STR39##  "         C.sub.18 H.sub.19 NO.sub.4                                                             313.34                                                                             117                                                                                7  68.99                                                                             6.11                                                                               4.47                                                                             68.70                                                                             6.11                                                                               4.51              770017                                                                              ##STR40##  H         C.sub.18 H.sub.19 NO.sub.4                                                             313.34                                                                             115                                                                               73  68.99                                                                             6.11                                                                               4.47                                                                             68.83                                                                             6.39                                                                               4.39              760547                                                                              ##STR41##  "         C.sub.17 H.sub.16 FNO.sub.4                                                            317.31                                                                             147                                                                               84  64.34                                                                             5.08                                                                               4.41                                                                             64.20                                                                             4.91                                                                               4.17              760556                                                                              ##STR42##  "         C.sub.18 H.sub.16 F.sub.3 NO.sub.4                                                     367.32                                                                              89                                                                               59  58.85                                                                             4.39                                                                               3.81                                                                             58.63                                                                             4.31                                                                               3.82              760574                                                                              ##STR43##  H         C.sub.17 H.sub.16 BrNO.sub.4                                                           378.21                                                                             153                                                                               75  53.98                                                                             4.26                                                                               3.70                                                                             53.81                                                                             4.17                                                                               3.46              760548                                                                              ##STR44##  "         C.sub.17 H.sub.16 ClNO.sub.4                                                           "   130                                                                               67  "  "  "  61.02                                                                             4.89                                                                               4.32              760729                                                                             "           CONHCH.sub.3                                                                             C.sub.19 H.sub.19 ClN.sub.2 O.sub.5                                                    390.82                                                                             109                                                                               71  58.39                                                                             4.90                                                                               7.17                                                                             58.33                                                                             4.89                                                                               7.10              760537                                                                              ##STR45##  H         C.sub.18 H.sub.19 NO.sub.4                                                             313.34                                                                             135                                                                               56  68.99                                                                             6.11                                                                               4.47                                                                             69.05                                                                             6.25                                                                               4.42              760533                                                                              ##STR46##  H         "       "   123                                                                               62  "  "  "  69.20                                                                             6.37                                                                               4.60              760881                                                                              ##STR47##  H         C.sub.18 H.sub.16 N.sub.2 O.sub.4                                                      324.32                                                                             159                                                                               76  66.66                                                                             4.97                                                                               8.64                                                                             66.62                                                                             4.95                                                                               8.71              760622                                                                              ##STR48##  H         C.sub.17 H.sub.16 N.sub.2 O.sub.6                                                      344.31                                                                             158                                                                               70  59.30                                                                             4.68                                                                               8.14                                                                             59.02                                                                             4.80                                                                               8.22              760676                                                                             "           CONHCH.sub.3                                                                             C.sub.19 H.sub.19 N.sub.3 O.sub.7                                                      401.36                                                                             153                                                                               89  56.85                                                                             4.77                                                                              10.47                                                                             56.64                                                                             4.63                                                                              10.53              760937                                                                             4 OCH.sub.2 H         C.sub.19 H.sub.22 N.sub.2 O.sub.4                                                      342.38                                                                             160                                                                               56  66.65                                                                             6.48                                                                               8.18                                                                             66.61                                                                             6.35                                                                               8.29                   ##STR49##                                                                 760432                                                                              ##STR50##  H         C.sub.17 H.sub.16 FNO.sub.4                                                            317.31                                                                             154                                                                               79  64.34                                                                             5.08                                                                               4.41                                                                             64.36                                                                             5.10                                                                               4.49              760717                                                                             "           CONHCH.sub.3                                                                             C.sub.19 H.sub.19 FN.sub.2 O.sub.5                                                     374.36                                                                             128                                                                               66  60.96                                                                             5.12                                                                               7.48                                                                             60.97                                                                             5.18                                                                               7.53              760453                                                                              ##STR51##  H         C.sub.16 H.sub. 16 FNO.sub.4                                                           317.31                                                                             141                                                                               81  64.34                                                                             5.08                                                                               4.41                                                                             64.60                                                                             5.01                                                                               4.33              760730                                                                             "           CONHCH.sub.3                                                                             C.sub.19 H.sub.19 FN.sub.2 O.sub.5                                                     374.36                                                                             112                                                                               50  60.96                                                                             5.12                                                                               7.48                                                                             60.99                                                                             5.19                                                                               7.77              760409                                                                              ##STR52##  CONHCH.sub.3                                                                             C.sub.19 H.sub.20 N.sub.2 O.sub.5                                                      356.37                                                                             118                                                                               82  64.03                                                                             5.66                                                                               7.86                                                                             64.04                                                                             5.74                                                                               7.97              760723                                                                             "                                                                                           ##STR53##                                                                               C.sub.21 H.sub.24 N.sub.2 O.sub.5                                                      384.42                                                                             132                                                                               83  65.61                                                                             6.29                                                                               7.29                                                                             65.91                                                                             6.83                                                                               7.12              760728                                                                              ##STR54##  CONHCH.sub.3                                                                             C.sub.19 ClN.sub.2 O.sub.5                                                             390.81                                                                             148                                                                               68  58.39                                                                             4.90                                                                               7.17                                                                             58.38                                                                             5.08                                                                               6.92              760809                                                                              ##STR55##  "         C.sub.19 H.sub.19 BrN.sub.2 O.sub.5                                                    435.27                                                                             109                                                                               54  52.43                                                                             4.40                                                                               6.44                                                                             52.58                                                                             4.41                                                                               6.51              760652                                                                             4 OCH.sub.2 COOH.sub.3                                                                     H         C.sub.13 H.sub.15 NO.sub.5                                                             265.26                                                                             148                                                                               66  58.86                                                                             5.70                                                                               5.28                                                                             58.56                                                                             5.69                                                                               5.17              760733                                                                             "           CONHCH.sub.3                                                                             C.sub.15 H.sub. 18 N.sub.2 O.sub.6                                                     322.31                                                                             102                                                                               62  55.89                                                                             5.63                                                                               8.69                                                                             55.63                                                                             5.76                                                                               8.60              770054                                                                             4 CHO       H         C.sub.11 H.sub.11 NO.sub.4                                                             219.20                                                                             123                                                                               35  59.72                                                                             5.01                                                                               6.33                                                                             59.49                                                                             4.66                                                                               6.20              760670                                                                             4 COCH.sub.3                                                                               H         C.sub.12 H.sub.13 NO.sub.4                                                             235.23                                                                             155                                                                               63  61.27                                                                             5.57                                                                               5.95                                                                             61.44                                                                             5.63                                                                               5.96              760731                                                                             "           CONHCH.sub.3                                                                             C.sub.14 H.sub.16 N.sub.2 O.sub.5                                                      292.28                                                                             130                                                                               49  57.53                                                                             5.52                                                                               9.59                                                                             57.23                                                                             5.27                                                                               9.43              __________________________________________________________________________

                                      table ii                                     __________________________________________________________________________      ##STR56##                                                                                          mole-                                                                               Melting  Elementary analysis                         Code         Empirical                                                                              cular                                                                               point                                                                               Yield                                                                              Calculated (%)                                                                          Obtained (%)                       Number                                                                              R       formula weight                                                                              (° C.)                                                                       (%) C  H  N  C  H  N                            __________________________________________________________________________     760472                                                                              4-SC.sub.4 H.sub.9 (n)                                                                 C.sub.13 H.sub.21 NO.sub.2 S                                                           255.37                                                                              <50  51  61.14                                                                             8.29                                                                              5.49                                                                              60.89                                                                             8.28                                                                               5.34                        760498                                                                              4-SC.sub.3 H.sub.7 (iso)                                                               C.sub.12 H.sub.19 NO.sub.2 S                                                           241.35                                                                              *1   59  59.72                                                                             7.94                                                                              5.80                                                                              59.23                                                                             8.54                                                                               5.94                        760599                                                                              4-SC.sub.3 H.sub.7 (n)                                                                 "       "    *2   48  "  "  "  59.60                                                                             8.25                                                                               5.48                        760982                                                                               ##STR57##                                                                             C.sub.15 H.sub.23 NO.sub.2 S                                                           281.41                                                                              82   63  64.02                                                                             8.24                                                                              4.98                                                                              63.86                                                                             8.42                                                                               4.98                        760464                                                                               ##STR58##                                                                             C.sub.13 H.sub.20 N.sub.2 O.sub.2                                                      236.31                                                                              125  20  66.07                                                                             8.53                                                                              11.86                                                                             65.78                                                                             8.49                                                                              12.02                        760355                                                                               ##STR59##                                                                             C.sub.14 H.sub.22 N.sub.2 O.sub.2                                                      250.33                                                                              86   23  67.17                                                                             8.86                                                                              11.19                                                                             67.47                                                                             9.14                                                                              11.02                        760732                                                                              4-CH.sub.3 CO                                                                          C.sub.11 H.sub.15 NO.sub.3                                                             209.24                                                                              135  48  63.14                                                                             7.23                                                                              6.69                                                                              63.17                                                                             7.54                                                                              7.06                         __________________________________________________________________________      *1: Eb.sub.0.04 = 250° C.                                               *2: Eb.sub.0.01 = 250° C.                                         

The compounds of formula (I) were studied on laboratory animals and showed activities in the psychotropic field, as potential antidepressants.

These activities show up in the following tests.

Test A

Potentiation in a mouse of generalised trembling caused by an intraperitoneal injection (200 mg/kg) of dl-5-hydroxytryptophane, according to the mode of operation described by GOURET C. and RAYNAUD G. in the J. Pharmacol. (PARIS), (1974), 5, 231.

Test B

Antagonism in relation to ptosis observed one hour after an intravenous injection (2 mg/kg) of reserpine was given to a mouse, according to the mode of operation described by GOURET C. and THOMAS J. in J. Pharmacol. (PARIS), (1973), 4, 401.

Test C

Diminution in the density of pontogeniculo-occipital points (P.G.O.) caused by injecting a cat with 0.5 mg/kg of reserpine, according to the mode of operation described by COSTON A. and GOURET C. in J. Pharmacol. (PARIS), (1976), 7, 409.

The results of these three tests as well as those of a reference substance TOLOXATONE are given in table III below:

                                      TABLE III                                    __________________________________________________________________________     Tested   Test A    Test B    Test C                                            compounds                                                                               50 DE (mg/kg/p.o.)                                                                       50 DE (mg/kg/p.o.)                                                                       50 DE (mg/kg/p.o.)                                __________________________________________________________________________     a/ According to the invention                                                  740704   42        12        52                                                740512   68        32        50                                                750710   62        100       14                                                740711   19        26        --                                                750341   100       41        22                                                740564   38        42        16                                                740511   55        17        40                                                760271   20        11        11                                                760395   39        28        160                                               760133   11        7.2       4.5                                               760311   27        32        9                                                 760375   39        28        160                                               760474   42        68        14                                                760082   22        18        8.4                                               760786   >50       40        25.5                                              760466   40        32        8.25                                              760473   41        22        11.5                                              760600   19        15.4      6.26                                              760621   100       42        40                                                760037   16        40        5.4                                               760116   60        50        15                                                760303   9         14        6.9                                               760304   5         5         6.1                                               760414   13        3         5.5                                               760396   12        1.4       20                                                760549   26        11        85                                                760314   19        18        12                                                760104   48        44        >50                                               760662   48        17.5      23                                                760712   48        25        35                                                760306   14        29        2.5                                               760827   15        10        5.2                                               760650   25.5      3.4       7.03                                              760535   28        50        5.1                                               760536   8.6       15        6.3                                               760307   8         14        5                                                 760658   >12.5     27        13.9                                              760877   25        25        5.6                                               760167   9.5       3.3       15.2                                              760337   6         5         120                                               760317   25        17        45                                                760556   5         3.2       14.1                                              760574   21        22        >50                                               760548   4.4       3.4       33.5                                              760729   >12.5     23        50                                                760537   35        17        37.5                                              760533   41        54        51                                                760881   12.5      5         29                                                760622   5.5       2.1       40                                                760676   >12.5     6.25      22                                                760432   3.8       2         24                                                760717   >12.5     12.5      >50                                               760453   5.5       7         11.6                                              760409   100       7         >50                                               760723   >50       17.5      >50                                               760652   7.1       2.8       13                                                760651   5.5       2.5       1.5                                               760660   >12.5     31        12.3                                              760670   21        10        14                                                760731   >25       15        17.5                                              b/ Reference                                                                   TOLOXATONE                                                                              60        50        28                                                __________________________________________________________________________

as can be seen from the preceding results and those given in table IV below, the difference between lethal doses and active pharmacological doses is sufficient for the compounds of the invention to be used in therapeutics.

                  TABLE IV                                                         ______________________________________                                                  Acute toxicity in mice                                                Tested     Dose administered                                                                            Mortality                                                                               50 DL                                        compounds  (mg/kg/p.o.)  (%)      (mg/kg/p.o.)                                 ______________________________________                                          a/ according to                                                                 the invention                                                                740704     2000          0        --                                           740711     1000          0        --                                           740564     --            --       >1000                                        760271     --            --        1050                                        760082     --            --       >2000                                        760037     --            --       >2000                                        760304     --            --       >2000                                        760167     --            --       >2000                                        b/ reference                                                                   TOLOXATONE --            --        1850                                        ______________________________________                                    

As can be seen from the preceding tables the compounds of formula (I) have an activity superior or equal to that of the reference compound.

They are indicated in endogene and exogene depressive conditions, and will ge given orally in the form of tablets, pills, gelules with a dosage of 500 mg/day on average of active constituent. 

What we claim is:
 1. A compound having the formula ##STR60## wherein n is 1 or 2; when n is 1, R₆ is H, o-F, o-CH₃, m-Cl, m-F, m-CH₃, m-CF₃, p-Cl, p-Br, p-F, p-CN, p-NO₂ ##STR61## and when n is 2, R₆ is H.
 2. A compound according to claim 1, having the formula ##STR62##
 3. A compound according to claim 1, having the formula ##STR63##
 4. A compound according to claim 1, having the formula ##STR64##
 5. A compound according to claim 1, having the formula ##STR65##
 6. A compound according to claim 1, having the formula ##STR66##
 7. A compound having the formula ##STR67##
 8. A compound having the formula ##STR68## wherein R₅ is cyclohexyl, cyclohexylmethyl, acetylmethyl or cyanomethyl.
 9. A compound according to claim 8, having the formula ##STR69##
 10. A compound having the formula ##STR70## wherein R₅ is alkene-2-yl having 3 to 5 carbon atoms, butene-3-yl or cyclohexene-1 methyl.
 11. A compound according to claim 10, having the formula ##STR71##
 12. A compound having the formula ##STR72## wherein R₅ is propargyl or butyne-2-yl.
 13. A compound having the formula ##STR73## wherein R is selected from the group consisting of OC₃ H₇ (n), ##STR74##
 14. A compound having the formula ##STR75## wherein R₄ is alkyl having 1 to 4 carbon atoms or cyclohexyl.
 15. A compound having the formula ##STR76## wherein R is --NO₂, --CN, --CHO or --COCH₃.
 16. A compound having the formula ##STR77## 